Vine Jr. was first educated at reservation schools. Deloria graduated from Kent School in 1951. He graduated from Iowa State University in 1958 with a degree in general science.[3] Deloria served in the Marines from 1954 through 1956.[4]

In 1964, Deloria was elected executive director of the National Congress of American Indians.[5] During his three-year term, the organization went from bankruptcy to solvency, and membership went from 19 to 156 tribes.[6] Through the years, he was involved with many Native American organizations. Beginning in 1977, he was a board member of the National Museum of the American Indian, which established its first center at the former United States Custom House in New York City.

In 1969, Deloria published his first of more than twenty books, entitled Custer Died for Your Sins: An Indian Manifesto. This book became one of Deloria's most famous works. In it, he addressed stereotypes of Indians and challenged white audiences to take a new look at the history of United States western expansion, noting its abuses of Native Americans.[7] The book was released the year that students of the Alcatraz-Red Power Movement occupied Alcatraz Island to seek construction of an Indian cultural center, as well as attention in gaining justice on Indian issues, including recognition of tribal sovereignty. Other groups also gained momentum, with organizations such as the American Indian Movement staging events to attract media and public attention for education.

The book helped draw attention to the Native American struggle. Focused on the Native American goal of sovereignty without political and social assimilation, the book stood as a hallmark of Native American Self-Determination at the time. The American Anthropological Association sponsored a panel in response to Custer Died for Your Sins. The book was reissued in 1988 with a new preface by the author, noting, "The Indian world has changed so substantially since the first publication of this book that some things contained in it seem new again."

Deloria wrote and edited many subsequent books and 200 articles, focusing on issues as they related to Native Americans, such as education and religion.[4] In 1995, Deloria argued in his book Red Earth, White Lies that the Bering Strait Land Bridge never existed, and that the ancestors of the Native Americans had not migrated to the Americas over such a land bridge, as has been claimed by most archaeologists, anthropologists, linguists and other scholars. Rather, he asserted that the Native Americans may have originated in the Americas, or reached them through transoceanic travel, as some of their creation stories suggested.[8]

Deloria's position on the age of certain geological formations, the length of time Native Americans have been in the Americas, their possible coexistence with dinosaurs, etc. were influential in the development of American Indian defenses against scientific racism. This generally rejects scientific explanations of origins of indigenous peoples in the Americas that contradict American Indian accounts.[8][9] Deloria argued that scientists are virtually incapable of independent thinking and are hobbled by their reverence for orthodoxy. He wrote that scientists characteristically persecute those who dare to advance unorthodox views, and that science is thus, essentially a religion.[10] Deloria has been criticized for his embrace of American Indian traditional histories by such scholars as Bernard Ortiz de Montellano and H. David Brumble, who say such views are not supported by the scientific and physical evidence, and contribute to problems of pseudoscience.[11]

Deloria often cited American Indian creation accounts and oral traditions in support of his views relating to science. He also relied on Hindu creationists, such as Michael Cremo.[12]

Nicholas Peroff wrote that "Deloria has rarely missed a chance to argue that the realities of precontact American Indian experience and tradition cannot be recognized or understood within any conceptual framework built on the theories of modern science. And in fact, it is certainly true that no one, with or without the aid of scientific theories and concepts, can, in any absolute meaning of the word, know what life was like as a member of the Menominee Tribe six hundred years ago. But we can imagine what it was like."[13]

His first tenured position was as Professor of Political Science at the University of Arizona, which he held from 1978 to 1990. While at UA, Deloria established the first master's degree program in American Indian Studies in the United States. Such recognition of American Indian culture in existing institutions was one of the goals of the Alcatraz-Red Power Movement.[4] Numerous American Indian studies programs, museums and collections, and other institutions have been established since Deloria's first book was published.